Heterocyclic amino substituted heteroaryl fused pyridines; GABA brain receptor ligands

ABSTRACT

Disclosed are compounds of the formula                    
     or the pharmaceutically acceptable non-toxic salts thereof wherein: 
     n is an integer from 0 to 3; 
     the C ring is aryl or heteroaryl; 
     X is CH, N, or O 
     Z represents an electron pair, hydrogen, or (un)substituted heterocycle, aryl, or amido; 
     W is (un)substituted alkyl, aryl, or heteroaryl; 
     A and B are hydrogen or lower alkyl, 
     which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.

This application is a continuation of Ser. No. 29/259,146 which wasfiled Feb. 26, 1999 and issued as U.S. Pat. No. 6,166,203 which claimsbenefit of Ser. No. 60/076,099 which was filed Feb. 26, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to heterocyclic amino substituted heteroarylfused pyridines, and more specifically to such compounds thatselectively bind to GABAa receptors. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness. The interaction of heterocyclic amino substitutedheteroaryl fused pyridines of the invention with a GABA binding site,the benzodiazepines (BDZ) receptor, is described. This interactionresults in the pharmacological activities of these compounds.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 40 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. GABA mediates many of its actions througha complex of proteins localized both on cell bodies and nerve endings;these are called GABAa receptors. Postsynaptic responses to GABA aremediated through alterations in chloride conductance that generally,although not invariably, lead to hyperpolarization of the cell. Drugsthat interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA.

The 1,4-Benzodiazepines, such as diazepam, continue to be among the mostwidely used drugs in the world as anxiolytics, sedative-hypnotics,muscle relaxants, and anticonvulsants. A number of these compounds areextremely potent drugs; such potency indicates a site of action with ahigh affinity and specificity for individual receptors. Earlyelectrophysiological studies indicated that a major action ofbenzodiazepines was enhancement of GABAergic inhibition. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

With the discovery of the “receptor” for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior. Depending on the mode ofinteraction, these compounds are capable of producing a spectrum ofactivities (either sedative, anxiolytic, and anticonvulsant, orwakefulness, seizures, and anxiety).

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in thediagnosis and treatment of anxiety, sleep and seizure disorders,overdose with benzodiazepine drugs and for enhancement of memory.Accordingly, a broad embodiment of the invention is directed tocompounds of general Formula I:

wherein:

the C ring represents a thiophene, pyridine, pyrazine, pyridazine, orpyrimidine ring, each of which is optionally mono- or disubstituted withlower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino, mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

n is 0 or an integer of from 1-3;

X is CH, nitrogen, or oxygen;

Z is an electron pair when X is oxygen;

Z is hydrogen;

Z is aryl or heteroaryl, each of which is optionally substituted withone, two or three groups independently selected from lower alkyl, loweralkoxy, amino, mono- or di(C₁-C₆)alkylamlno, or halogen; or

 where

Z is

Y is oxygen or sulfur;

R is lower alkyl, hydroxy, lower alkoxy, hydroxyalkyl, or aminoalkyl, ormono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl;

R is aryl or heteroaryl each of which is mono or disubstitutedindependently with halogen, thio, hydroxyl, lower alkyl, lower alkoxy,amino or mono- or di(C₁-C₆)alkylamino;

R is amino, optionally substituted with one or two groups independentlyselected from

lower alkyl, hydroxyalkyl, C₃-C₇ cycloalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;

heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted withone or two groups independently selected from halogen, thio, hydroxyl,lower alkyl, lower alkoxy, or amino; or

a C₃-C₇ carbocyclic group having, where up to two of which atoms of thecarbocyclic group are optionally hetero atoms selected from oxygen andnitrogen and where any atom of the carbocyclic group is optionallysubstituted with halogen, lower alkyl or lower alkoxy; or

R is a carbocyclic group having from 3-7 members, where up to three ofwhich members are optionally hetero atoms selected from oxygen andnitrogen and where any member of the carbocyclic group is optionallysubstituted with halogen, lower alkyl, or lower alkoxy;

A and B are the same or different and represent hydrogen or lower alkyl;and

W is aryl or heteroaryl, each of which may be mono-, or di-, ortrisubstituted independently with halogen, hydroxyl, lower alkyl, loweralkoxy, amino, mono- or di(C₁-C₆)alkylamino, trifluoromethyl or nitro.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs of agonists, antagonistsor inverse agonists for GABAa brain receptors. In other words, while thecompounds of the invention all interact with GABAa brain receptors, theydo not display identical physiological activity. Thus, these compoundsare useful in the diagnosis and treatment of anxiety, sleep and seizuredisorders, overdose with benzodiazepine drugs and for enhancement ofmemory. For example, these compounds can be used to treat overdoses ofbenzodiazepine-type drugs as they would competitively bind to thebenzodiazepine receptor.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by general Formula I set forth above or the pharmaceuticallyacceptable non-toxic salts thereof.

In addition, the present invention also encompasses compounds of FormulaIIa and IIb

wherein A, B, W, X, Z, and n are as defined above for Formula I; and

R_(a) and R_(b) independently represent hydrogen, lower alkyl, C₁-C₆alkoxy, hydroxy, halogen, amino, mono- or di(C₁-C₆)alkylamino, ortrifluoromethyl.

Preferred compounds of Formula IIa and IIb are R_(a) and R_(b) arehydrogen, and a where W is phenyl or 2-, 3-, or 4-pyridyl, each of whichis optionally mono or disubstituted independently with halogen,hydroxyl, lower alkyl, or lower alkoxy. Other preferred compounds ofFormula IIa and IIb are those where X is CH and Z is or 2-imidazolyl, or1,2,4-triazol-3-yl,

Other preferred compounds of the invention are those of Formula II wheren is 2 or 3.

Other preferred compounds of Formula IIa and IIb are where A and B arehydrogen or methyl.

Preferred Z groups in Formulae IIa and IIb include Z-1, Z-2, Z-3, Z-4,Z-5, Z-6, Z-7, Z-8, and Z-9 groups.

where R_(z), and R_(y) are independently hydrogen, C₁-C₆ alkyl, 2-, 3-,or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, or 2- or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl-(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

where E is a bond or C₁-C₆ alkylene, each of Rp and R_(p)′ areindependently hydroxy, halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. PreferredR_(p) groups are fluoro, more preferably 4-fluoro, and chloro. PreferredR_(p)′ groups are hydrogen, C₁-C₂ alkoxy, C₁-C₂ alkyl, fluoro, morepreferably 4-fluoro, and chloro. Preferred E groups are a bond and C₂alkylene.

where G is 2-, 3-, or 4-pyridyl, each of which is optionally mono- ordisubstituted with C₁-C₆ alkyl, C_(l)-C₆ alkoxy, or halogen.

where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl, 2-, 3-,or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆) alkyl, 2-, or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

where R_(e) is hydrogen or C₁-C₆ alkyl. Preferred R_(e) groups in Z-7are hydrogen atoms.

where each R_(e) is independently hydrogen or C₁-C₆ alkyl. PreferredR_(e) groups in Z-8 are hydrogen and methyl.

where R is C₁-C₆ alkyl.

The present invention also enc ompasses compounds of Formula IIIa andFormula IIIb:

wherein W, X and Z are as defined above for Formula I; and R_(a) ishydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino, mono- ordi(C₁-C₆)alkylamino, or trifluoromethyl.

Preferred compounds of Formula IIIa and IIIb are where W is phenyl or2-, 3-, or 4-pyridyl, each of which is optionally mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy.

Preferred Z groups in Formulae IIIa and IIIb include Z-1, Z-2, Z-3, Z-4,Z-5, Z-6, Z-7, Z-8, and Z-9 groups.

where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl, 2-, 3-,or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, or 2- or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl-(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

where E is a bond or C₁-C₆ alkylene, each of Rp and R_(p)′ areindependently hydroxy, halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. PreferredR_(p) groups are fluoro, more preferably 4-fluoro, and chloro. PreferredR_(p)′ groups are hydrogen, C₁-C₂ alkoxy, C₁-C₂ alkyl, fluoro, morepreferably 4-fluoro, and chloro. Preferred E groups are a bond and C₂alkylene.

where G is 2-, 3-, or 4-pyridyl, each of which is optionally mono- ordisubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen.

where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl, 2-, 3-,or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, 2-, or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

where R_(e) is hydrogen or C₁-C₆ alkyl. Preferred Re groups in Z-7 arehydrogen atoms.

where each R_(e) is independently hydrogen or C₁-C₆ alkyl. PreferredR_(e) groups in Z-8 are hydrogen and methyl.

where R is C₁-C₆ alkyl.

The present invention also encompasses compounds of Formula IV:

wherein W, X, and Z are as defined above in Formula I; and

A, B, C, and D are independently CR₁ or nitrogen, provided that no morethan two of A, B, C, and D are nitrogen simultaneously; and

R₁ is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy,hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, or arylalkyl.

Preferred compounds of Formula IV are where W is phenyl or 2-, 3-, or4-pyridyl each of which is optionally mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy.

Still other preferred compounds of Formula IV are those where A isnitrogen and B, C, and D are hydrogen.

Preferred Z groups in Formula IV include Z-1, Z-2, Z-3, Z-4, Z-5, Z-6,Z-7, Z-8, and Z-9 groups.

where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl, 2-, 3-,or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, or 2- or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl-(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

where E is a bond or C₁-C₆ alkylene, each of Rp and R_(p)′ areindependently hydroxy, halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. PreferredR_(p) groups are fluoro, more preferably 4-fluoro, and chloro. PreferredR_(p)′ groups are hydrogen, C₁-C₂ alkoxy, C₁-C₂ alkyl, fluoro, morepreferably 4-fluoro, and chloro. Preferred E groups are a bond and C₂alkylene.

where G is 2-, 3-, or 4-pyridyl, each of which is optionally mono- ordisubstituted with C₁-C₆ alkyl, C₁-C₆, alkoxy, or halogen.

where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl, 2-, 3-,or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, 2-, or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

where R_(e) is hydrogen or C₁-C₆ alkyl. Preferred R_(e) groups in Z-7are hydrogen atoms.

where each R_(e) is independently hydrogen or C₁-C₆ alkyl. PreferredR_(e) groups in Z-8 are hydrogen and methyl.

where R is C₁-C₆ alkyl.

Preferred compounds of the invention are encompassed by the followingformulae:

where W, X, and Y are as defined above in Formula I;

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl; and

R₂ and R₃ are the same or different and represent

hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalky,or amidoalkyl;

aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which may bemono or disubstituted independently on the aryl group with halogen,thio, hydroxyl, lower alkyl, lower alkoxy, or amino; or

a C₃-C₇ carbocyclic or C₃-C₇ carbocyclic (C₁-C₆) alkyl group having from3-7 members, where up to two of which members are optionally heteroatoms selected from oxygen and nitrogen and where any member of thecarbocyclic group is optionally substituted with halogen, lower alkyl orlower alkoxy.

More preferred compounds of Formula Va and Vb are those where R₂ ishydrogen and where W is aryl or heteroaryl mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy.

Other preferred compounds are represented by Formula VI.

where W, and X are as defined above in Formula I and wherein:

A, B, C, and D are independently CR₁ or nitrogen, provided that at leastone but not more than two of A, B, C, and D are nitrogen simultaneously;

R₁ is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy,hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, or arylalkyl; and

R₂ and R₃ are the same or different and represent

hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalky,or amidoalkyl;

aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which may bemono or disubstituted independently on the aryl group with halogen,thio, hydroxyl, lower alkyl, lower alkoxy, or amino, or

a carbocyclic or carbocyclic(C₁-C₆)alkyl group having from 3-7 membersin the carbocyclic portion, where up to two of which members areoptionally hetero atoms selected from oxygen and nitrogen and where anymember of the carbocyclic group is optionally substituted with halogen,lower alkyl or lower alkoxy.

More preferred compounds of Formula VI are where W is phenyl or 2-, 3-,or 4-pyridyl each of which is optionally mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy;where A is nitrogen and B, C, and D are hydrogen; and where R₂ ishydrogen and R₃ is hydrogen or lower alkyl.

Still other preferred compounds of the invention are represented byFormula VIIa and VIIb.

where W and X are as above in Formula I and wherein

n is the integer 2 or 3;

Z is an electron pair when X is oxygen;

Z is hydrogen;

Z is aryl optionally substituted with one or two groups selected fromlower alkyl, lower alkoxy, or halogen; or

 where

Z is

Y oxygen or sulfur;

R is amino, optionally substituted with one or two groups selected fromlower alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl,amidoalkyl, heteroaryl.

More preferred compounds of Formula VIIa and VIIb are where where Y isoxygen and W is aryl or heteroaryl mono or disubstituted independentlywith halogen, hydroxyl, lower alkyl, or lower alkoxy.

The present invention also encompasses compounds of Formula VIIIa andFormula VIIIb:

wherein W and X are as defined above for Formula I;

R_(x) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

A is nitrogen or CH; and

R_(x) is hydrogen, lower alkyl, hydroxy, lower alkoxy, hydroxyalkyl, oraminoalkyl, or mono- or di(C₁-C₆)alkylamino (C₁-C₆)alkyl.

Preferred compounds of Formula VIIIa and VIIIb are where W is phenyl or2-, 3-, or 4-pyridyl, each of which is optionally mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy.Other preferred compounds of Formulae VIIIa and b are those where X isCH and A is CH. More preferred compounds of Formula VIIIa and b where Ais CH are those where R_(x) is hydrogen, methyl or ethyl. Particularlypreferred compounds of Formulae VIIIa and b where A is CH are thosewhere W is phenyl optionally substituted with one or two groups selectedfrom halogen, preferably fluoro and chloro, methyl, ethyl, or amino.

Still other preferred compounds of Formulae VIIIa and b are those whereX is CH and A is nitrogen. More preferred compounds of Formula VIIIa andb where A is nitrogen are those where R_(x) is hydrogen, methyl orethyl. Particularly preferred compounds of Formulae VIIIa and b where Ais nitrogen are those where W is phenyl optionally substituted with oneor two groups selected from halogen, preferably fluoro and chloro,methyl, ethyl, or amino.

By “alkyl” and “lower alkyl” in the present invention is meant straightor branched chain alkyl groups having 1-6 carbon atoms, such as, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By “alkoxy” and “lower alkoxy” in the present invention is meantstraight or branched chain alkoxy groups having 1-6 carbon atoms, suchas, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy,hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine. Preferred halogens are fluorine, bromine,and chlorine.

By heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or7-membered rings containing at least one and up to four heteroatomsselected from nitrogen, oxygen, or sulfur. Such heteroaryl groupsinclude, for example, thienyl, furanyl, thiazolyl, imidazolyl,(is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl,benzimidazolyl, benzoxazolyl. Preferred heteroaryl groups arepyrimidinyl, pyridyl, imidazolyl, naphthyridinyl, and benzimidazolylgroups that are optionally substituted as described herein.

The heteroaryl groups of the invention may be substituted with up tofour groups selected from, for example, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, halogen, thio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, C₃-C₇ cycloalkyl, alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, and amidoalkyl. Other heteroaryl substituents include,for example, phenyl, pyridyl, pyrimidiyl, imidazolyl, morpholinyl,piperidinyl, piperazinyl, pyrrolyl, and pyrrolidinyl.

By 1H-1,4-Diazepine is meant the structure

By aryl is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy. Preferred aryl groups are phenyl andnapthyl groups that are optionally substituted as described herein.

The aryl groups of the invention may be substituted with up to fourgroups selected from, for example, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, halogen, thio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, C₃-C₇ cycloalkyl, alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, and amidoalkyl. Other aryl substituents include, forexample, phenyl, pyridyl, pyrimidiyl, imidazolyl, morpholinyl,piperidinyl, piperazinyl, pyrrolyl, and pyrrolidinyl.

Representative C₃-C₇ carbocyclic or C₃-C₇ carbocyclic(C₁-C₆)alkyl groupsthat include one or two oxygen or nitrogen atoms are, for example,morpholino, pyrrolo, imidazolyl, piperidinyl, piperazinyl, pyrazinyl,pyranyl, tetrahydropyanyl, pyrrolidinyl, 1H-1,4-diazepinyl, andpyrrolinyl. These groups are optionally substituted with one or twogroups, preferably one group, selected from halogen, lower alkyl andlower alkoxy.

Representative compounds of the invention are shown below in Table 1.

TABLE 1

Compound 1

Compound 5

Compound 7

Compound 9

Compound 10

Compound 13

Compound 20

Compound 21

Compound 29

Compound 33

Compound 35

Compound 38

Compound 45

Compound 52

Compound 59

Compound 62

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid and base addition salts. Inaddition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutically acceptable salts include salts of acids suchas hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH₂)_(n)-COOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

The compounds of Formula I and their salts are suitable for thediagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive andseizure disorders, and overdose with benzodiazepine drugs and forenhancement of alertness, both in human and non-human animals anddomestic pets, especially dogs and cats and farm animals such as sheep,swine and cattle.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. guch materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It will be convenient toformulate these animal feed and drinking water compositions with amullet-dose of the drug so that the animal takes in an appropriatequantity of the composition along with its diet. It will also beconvenient to present the composition as a premix for addition to thefeed or drinking water.

The compounds of the invention may be prepared using the syntheticroutes outlined in the following schemes.

where A, B, the C ring, W, Y, R, R₂, R₃ and n are as defined above inFormula I.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. For example, certain groups, e.g., nitrogen and hydroxy, mayrequire protection during the synthesis.

As shown in Scheme I, an aniline is reacted with a suitable β-keto esterin the presence of an acid, such as, for example, P-toluenesulfonicacid, to form a 4-hydroxypyridine which is subsequently converted to the4-chloropyridine upon treatment with a nucleophilic halogenating reagentsuch phosphorus oxychloride. The resulting chloride is reacted with thedesired 1,4-diheterocarbocycle, such as a piperazine or1,4-diazaperhydropine at elevated temperatures to form the N-alkylatedproduct. The piperdine can then be further alkylated with a desiredisocyanate or isothiocyanate, such as, for example, methyl isocyanate,to form the target compound.

As shown in Scheme II, a 4-chloropyridine is reacted with a reagent suchas ethyl 4-piperdinecarboxylate at elevated temperatures to form theN-alkylated ester. The ester is treated with an amine, such asmethylamine, in the presence of a base such as sodium hydroxide to formthe resulting amide.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

Representative examples of methods for preparing intermediates of theinvention are set forth below.

EXAMPLE 1 1. 5-(4-Fluorophenyl)-thieno[3,2-b]pyridin-7-ol

A mixture of 3-amino-2-thiophenecarboxylic acid (8 g, 49 mmol), ethyl4-fluorobenzoylacetate (9.6 g, 49 mmol), and p-toluenesulfonic acidmonohydrate (0.2 g, 1 mmol) in toluene (100 mL) is refluxed for 20 hourswith a Dean-Stark water trap to remove produced water. The mixture iscooled to room temperature. The resulting precipitate is filtered andwashed with diethyl ether. The solid is dissolved in diphenyl ether (80mL) and heated at 220° C. for 2 hours. The reaction solution is thencooled to room temperature and diluted with diethyl ether; theprecipitate is filtered and washed with diethyl ether to give5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (2 g, 17% yield) as browncrystalline needles, m.p. 316-318° C.

2. 7-Chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine

A solution of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (1.6 g) inphosphorus oxychloride (50 mL) is refluxed for 3 hours. After the excessamount of phosphorus oxychloride is removed under vacuum, the residue istreated with ethyl acetate (20 mL) and NaOH (2N, 20 mL). The mixture isthen extracted with ethyl acetate (3×20 mL). The combinded organiclayers are washed with brine and dried over MgSO₄. Evaporation of thesolvent affords 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (1.5 g,88% yield) as a white solid, m.p. 119-121° C.

3.1-(5-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide

A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68 mg,0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate (21mg, 0.26) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heated in anoil bath at 160° C. for 4 hours. The reaction mixture is then cooled anddiluted with EtAc (15 mL), transferred to a separatory funnel, andwashed with water (3×15 mL). The organic layer is dried over sodiumsulfate and concentrated. The residue is recrystalized with ethylacetate to give1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide(55 mg, 60% yield) as a white solid. This material is dissolved in ethylacetate and HCl saturated ethyl acetate (2 mL) is added. The solution isconcentrated to afford the HCl salt as a greasy oil.1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 3) is precipitated out of an ether solution,collected by filtration, washed with ether, and dried in vacuo to affordthe final product. m.p. 303-305° C. (dec).

EXAMPLE 2 1. 4-Chloro-6-phenylthieno[2,3-b]pyridine

A mixture of 3-aminothiophene (4 g, 0.04 mole), ethyl benzoylacetate (11mL, 0.06 mole), toluene (100 mL), and p-toluene sulfonic acidmonohydrate (300 mg) is stirred and heated under reflux with aDean-Stark water trap at 120° C. for 16 hours. The reaction mixture isconcentrated, and diphenyl ether (30 mL) is added. After heating at 240°C. for 1 hour, the reaction mixture was allowed to cool to roomtemperature. The reaction mixture is diluted with hexane, and thesemi-solid collected is then purified by short silica gel column(CH₂Cl₂/MeOH/NH₄OH: 10:1:0.1). The resulting product,4-hydroxy-6-phenyl-thieno[2,3-b]pyridine, is treated with phosphorusoxychloride (30 mL) and heated under reflux for 3 hours. This mixture iscooled to room temperature, poured over ice, neutralized with 10 Nsodium hydyoxide, and extracted with methylene chloride (3×20 mL). Thecombined organic layers are dried over sodium sulfate and concentratedin vacuo. The residue is purified by chromatography to give4-chloro-6-phenylthieno[2,3-b]pyridine as a yellowish solid (1.1 g, 11%total yield), m.p. 83-85° C.

2. Ethyl 1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylate

A mixture of 4-chloro-6-phenyl-thieno[2,3-b]pyridine (200 mg, 0.82mmole) and ethyl isonipecotate (5 mL) is stirred and heated in an oilbath at 170° C. for 6 hours. The reaction mixture is cooled and purifiedon a preparative tlc plate to give ethyl1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylate (100 mg,33% yield) as a colorless oil.

EXAMPLE 3 N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide

A solution of1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acid ethylester (50 mg, 0.14 mmole), ethylamine (2 mL), and a catalytic amount ofsodium cynide in MeOH (10 mL) is heated in a sealed tube at 70° C. oilbath for 48 hours. The solvent is removed on rotary-evaporator. Theresulting residue is purified on a preparative tlc plate to give N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4 piperidinecarboxamide (20 mg,39% yield) as a colorless oil. This material is dissolved in ethylacetate (1 mL), diluted with HCl saturated ethyl acetate (2 mL), andconcentrated to afford N-ethyl1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamidehydrochloride (compound 1, 26 mg) as greasy oil. The salt is solidifiedwith ether, collected by filtration, washed with ether, and dried invacuo. m.p. >270° C. (dec).

EXAMPLE 4 1. 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperazine

A reaction mixture of 7-chloro-5-phenylthieno[3,2-b]pyridine (200 mg,0.82 mmole), piperazine (100 mg, 1.19 mmole) and phenol (1 g) is heatedunder N₂ at 160° C. oil bath for 3 hours. The mixture is cooled down toroom temperature, dilutied with EtAc (15 mL), transferred to aseparatory funnel, and extracted with 5% HCl solution (3×15 mL). Thecombined acidic extracts are basified using concentrated NH₄OH solutionand then extracted with CH₂Cl₂ (3×15 mL). The combined organic layersare dried over soduim sulfate and concentrated, and the crude residue ispurified on a preparative tlc plate to give1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperazine (90 mg, 37% yield) asa yellowish oil.

2. N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide

A reaction solution of1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazine (120 mg, 0.41 mmole)and methyl isocynate (0.5 mL) in toluene (10 mL) is heated in a 120° C.oil bath for 1 hour. The resulting solution is cooled down to roomtemperature and concentrated. The crude residue is purified on apreparative tlc plate to give N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide (100 mg,69% yield) as a colorless oil. This material is dissolved in 1 mL ethylacetate. Ethyl acetate saturated with HCl (2 mL) is added and thesolution is then concentrated to afford 105 mg of N-methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 2) as a greasy oil. The salt is solidified withether, collected by filtration, washed with ether, and dried in vacuo.m.p. 185-190° C.

EXAMPLE 5 7-Chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine

A solution of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (1.6 g) inphosphorus oxychloride (50 mL) is refluxed for 3 hours. After the excessphosphorus oxychloride is removed under vacuum, the residue is treatedwith ethyl acetate (20 mL), and NaOH (2N, 20 mL). The mixture isextracted with ethyl acetate (3×20 mL) and the combined organic layersare washed with brine and dried over MgSO₄. Evaporation of the solventgives 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (1.5 g, 88%yield) as a white solid, m.p. 119-121° C.

EXAMPLE 6 5-(4-Fluorophenyl)-7-[4-(1H-imidazol-2-yl)-1-piperidinylthieno[3,2-b]pyridine

A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (146 mg,0.53 mmole), 4-(1H-imidazol-2-yl)piperidine hydrochloride (See U.S. Pat.No. 4,431,653) (100 mg, 0.53 mmole) and sodium acetate (50 mg) inethylene glycol (10 mL) is stirred and heated at 160° C. for 16 hours.It is then cooled, diluted with ethylacetate (15 mL), and washed withwater (3×15 mL). The organic layer is dried over sodium sulfate, andconcentrated. The residue is purified by preparative tlc plate to give5-(4-fluorophenyl)-7-[4-(1H-imidazol-2-yl)-1-piperidinylthieno[3,2-b]pyridine (36 mg, 18% yield) as a white solid, m.p. 95° C.(compound 63).

EXAMPLE 71-(5-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide

A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68 mg,0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate (21mg, 0.26 mmole) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heatedin an oil bath at 160° C. for 4 hours. The mixture is then cooled,diluted with ethyl acetate (15 mL), and washed with water (3×15 mL). Theorganic layer is dried over sodium sulfate, and concentrated. Theresidue is recrystalized from ethyl acetate to give1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide(Compound 64, 55 mg, 60% yield) as a white solid product (m.p. 251°C.-253° C.).

EXAMPLE 85-(4-Fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine

A suspension of1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide(100 mg, 0.32 mmole) in phosphorus oxochloride (5 mL) is refluxed for0.5 hours. After the excess phosphorus oxychloride is removed undervacuum, the residue is treated with ethyl acetate (5 mL), and ice-water(10 mL). The resulting mixture is subsequently extracted with ethylacetate (3×10 mL) and the combined organic layers are washed with brine,dried over sodium sulfate, and concentrated. The residue is thendissolved in toluene (5 mL), then formic hydrazid (100 mg, 1.7 mmole),and formic acid (0.05 mL) are added. The reaction mixture is refluxedfor 16 hours, cooled, diluted with ethyl acetate (15 mL), and washedwith water (3×15 mL). The organic layer is dried over sodium sulfate,and concentrated.

The residue is purified by preparative tlc plate to give5-(4-fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine(7 mg, 6% yield) as a white solid. This material is dissolved in ethylacetate (1 mL), saturated with HCl (2 mL), and then concentrated toafford5-(4-fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridinehydrochloride (compound 65) as greasy oil.

The salt is solidified with ether, collected by filtration, washed withether and dried in vacuo, m.p. >300° C. (dec).

EXAMPLE 9

The following compounds were prepared essentially according to theprocedures set forth in Examples 1-8:

j)4-Pyridinylcarbonyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazinehydrochloride (compound 13), m.p. 215-217° C.

k) N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 14), m.p. >198-201° C.

l) N-n-Propyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 15), m.p. >130° C. (dec).

m) N-i-Propyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 16), m.p. 127-129° C. (dec).

n) N-n-Butyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 17), m.p. >93° C. (dec).

o) N-(3-Chloro-n-Propyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 18), m.p. 235-238° C. (dec).

p) N-Ethyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 19), m.p. >147° C. (dec).

q) N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarbothioamidehydrochloride (compound 20), m.p. >° C. (dec).

a)1-(5-(2-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide(compound 4), m.p. 194-195° C.

b)N-4-Picolyl-1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidedihydrochloride (compound 5), m.p. 176-178° C. (dec).

c) N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 6), m.p. >220° C. (dec).

d)4-Fluorophenylcarbonyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazinehydrochloride (compound 7), m.p. >174° C. (dec).

e) N-Methylhexahydro-4-(5-phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine) (compound 8),m.p. >220° C. (dec).

f) 4-(5-Phenylthieno[3,2-b]pyridin-7-yl)morpholine hydrochloride(compound 9), m.p. 195-198° C.

g) 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-[1H-1,4-diazepine]dihydrochloride (compound 10), m.p. >255° C. (dec).

h)N-Ethylhexahydro-4-(5-phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine)-1-carboxamidedihydrochloride (compound 11), m.p. >180° C. (dec).

i) N-Ethyl 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 12), m.p. >240° C. (dec).

r) 1-(2-Phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxylic acid ethylester hydrochloride (compound 21), m.p. >180° C. (dec).

s) N-Ethyl 1-(2-phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxamidehydrochloride (compound 22), m.p. >210° C. (dec).

t) N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 23), m.p. >260° C. (dec).

u) N-Propyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 24), m.p. 159-160° C. (dec).

v) 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 25), m.p. ° C. (dec).

w) N-t-Butyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 26), m.p. 270-272° C. (dec).

x) N-n-Butyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 27), m.p. 170-172° C. (dec).

y) N-Cyclopropyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 28), m.p. 199-201° C. (dec).

z) N-Cyclopentyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 29), m.p. 179-181° C. (dec).

aa) N-(2-Aminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 30), m.p. 176-178° C. (dec).

bb) N-(2-Ethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 31), m.p. >95° C. (dec).

cc) N-(2-Dimethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 32), m.p. >150° C. (dec).

dd) N-Glycinamidyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 33), m.p. 158-160° C. (dec).

ee) N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 34), m.p. >220° C. (dec).

ff) N-(2-Methoxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 35), m.p. 157-160° C. (dec).

gg) N-(3-Methoxypropyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 36), m.p. 147-149° C. (dec).

hh) N-Benzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 37), m.p. 163-165° C. (dec).

ii) N-2-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 38), m.p. 164-166° C. (dec).

jj) N-3-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 39), m.p. 236-238° C. (dec).

kk) N-4-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 40), m.p. 190-192° C. (dec).

ll) N-4-Methylbenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 41), m.p. 177-178° C. (dec).

mm) N-4-Ethoxybenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 42), m.p. >° C. (dec).

nn) N-4-Pyridylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 43), m.p. >° C. (dec).

oo) N-2-Thiophenylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 44), m.p. >230° C. (dec).

pp) N-2-Tetrahydrofuranylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 45), m.p. >210° C. (dec).

qq) 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acidethyl ester hydrochloride (compound 46), m.p. >° C. (dec).

rr) 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acidhydrochloride (compound 47), m.p. >° C. (dec).

ss)1-(5-(3-Methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 48), m.p. 133-135° C. (dec).

tt) N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 49), m.p. >230° C. (dec).

uu)1-(5-(4-Ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 50), m.p. 211-213° C. (dec).

vv) N-2-Pyridinylmethyl1-(5-(4-ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 51), m.p. 178-180° C. (dec).

ww)1-(5-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 52), m.p. >303° C. (dec).

xx) N-Methyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 53), m.p. >° C. (dec).

yy) N-Ethyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 54), m.p. 220-222° C. (dec).

zz) N-Propyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 55), m.p. 207-209° C. (dec).

aaa) N-(2-Aminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 56), m.p. 115-118° C. (dec).

bbb) N-(2-Dimethylaminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 57), m.p. 180-182° C. (dec).

ccc) N-(2-Hydroxyethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 58), m.p. 198-200° C. (dec).

ddd) N-(2-Methyoxypropyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 59), m.p. 179-180° C. (dec).

fff) N-Ethyl1-(5-(4-pyridyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 60), m.p. >227° C. (dec).

ggg) 1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylic acidmethyl ester hydrochloride (compound 61), m.p. >220° C. (dec).

hhh) N-Ethyl1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamidehydrochloride (compound 62), m.p. >270° C. (dec).

EXAMPLE 10

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor binding activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20′. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at −20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand0.5 nM (³H-RO15-1788 [³H-Flumazenil] specific activity 80 Ci/mmol), drugor blocker and buffer to a total volume of 500 ml. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice withfresh 0.05 M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total−Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to IC₅₀ or K_(i). The Ki ofthe compounds in this invention are less than 1 μM.

EXAMPLE 11

In addition, the following assay may be used to determine if thecompounds of the invention are agonists, antagonists, or inverseagonists, and, therefore, their specific pharmaceutical utility. Thefollowing assay can be employed to determine specific GABAa receptoractivity.

Assays are carried out as described in White and Gurley (NeuroReport 6:1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory(Receptors and Channels 3: 1-5, 1995) with modifications. Xenopus Laevisoocytes are enzymatically isolated and injected with non-polyadenylatedcRNA mixed in a ratio of 4:1:4 for human derived α, β, and γ subunits,respectively. For each subunit combination, sufficient message isinjected to result in current amplitudes of >10 nA when 1 μM GABA isapplied.

Electrophysiological recordings are carried out using the two electrodevoltage-clamp technique at a membrane holding potential of −70 mV.

Compounds are evaluated against a GABA concentration that evokes <10% ofthe maximal evokable GABA current. Each oocyte is exposed to increasingconcentrations of compound in order to evaluate a concentration/effectrelationship. Compound efficacy is expressed as a percent-change incurrent amplitude: 100*((Ic/I)−1), where Ic is the GABA evoked currentamplitude observed in the presence of compound and I is the GABA evokedcurrent amplitude observed in the absence of compound.

Specificity of a compound for the Ro15-1788 site is determined followingcompletion of the concentration/effect curve. After washing the oocytesufficiently to remove previously applied compound, the oocyte isexposed to GABA +1 μM Ro15-1788, followed by exposure to GABA +1 AMRo15-1788+compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in thepresence of Ro15-1788 is subtracted from the percent changes in currentamplitude observed in the absence of 1 μM Ro15-1788. These net valuesare used for the calculation of average efficacy and EC₅₀ values.

To evaluate average efficacy and EC₅₀ values, the concentration/effectdata are averaged across cells and fit to the logistic equation. Averagevalues are reported as mean±standard error.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound or pharmaceutically acceptable salt ofthe formula:

wherein: n is 0 or an integer of from 1-3; X is CH, nitrogen, or oxygen;Z is an electron pair when X is oxygen; Z is hydrogen, provided thatwhen X is CH, Z is not hydrogen; Z is aryl, which is unsubstituted orsubstituted with one or two groups independently selected from loweralkyl, lower alkoxy, or halogen; or

 where Z is Y is oxygen or sulfur; R is lower alkyl, hydroxy, loweralkoxy, hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each ofwhich is mono or disubstituted independently with halogen, thio,hydroxyl, lower alkyl, lower alkoxy, or amino; R is amino which isunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, or amidoalkyl; heteroaryl, arylalkyl orheteroarylalkyl, each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic group having from 3-7member atoms, where up to two of which atoms are heteroatoms selectedfrom oxygen and nitrogen and where any member of the carbocyclic groupis unsubstituted or substituted with halogen, lower alkyl or loweralkoxy; or R is a carbocyclic group having from 3-7 member atoms, whereup to three of which members are heteroatoms selected from oxygen andnitrogen and where any member of the carbocyclic group is unsubstitutedor substituted with halogen, lower alkyl, or lower alkoxy; A and B arethe same or different and represent hydrogen, or lower alkyl; and the Cring represents a thiophene, pyridine, or pyrimidine ring.
 2. Apharmaceutical composition comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: n is 0 or an integer of from 1-3;X is CH, nitrogen, or oxygen; Z is an electron pair when X is oxygen; Zis hydrogen, provided that when X is CH, Z is not hydrogen; Z is aryl orheteroaryl, each of which is unsubstituted or substituted with one ortwo groups independently selected from lower alkyl, lower alkoxy, orhalogen; or

 where Z is Y is oxygen or sulfur; R is lower alkyl, hydroxy, loweralkoxy, hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each ofwhich is mono or disubstituted independently with halogen, thio,hydroxyl, lower alkyl, lower alkoxy, or amino; R is amino which isunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, or amidoalkyl; heteroaryl, arylalkyl orheteroarylalkyl, each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic group having from 3-7member atoms, where up to two of which atoms are heteroatoms selectedfrom oxygen and nitrogen and where any member of the carbocyclic groupis unsubstituted or substituted with halogen, lower alkyl or loweralkoxy; or R is a carbocyclic group having from 3-7 member atoms, whereup to three of which members are heteroatoms selected from oxygen andnitrogen and where any member of the carbocyclic group is unsubstitutedor substituted with halogen, lower alkyl, or lower alkoxy; A and B arethe same or different and represent hydrogen, or lower alkyl; the C ringrepresents a thiophene, pyridine, or pyrimidine ring; and W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl.
 3. A pharmaceutical compositionaccording to claim 2 comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: n is 0 or an integer of from 1-3;X is CH, nitrogen, or oxygen; Z is an electron pair when X is oxygen; Zis hydrogen, provided that when X is CH, Z is not hydrogen; Z is arylwhich is unsubstituted or substituted with one or two groupsindependently selected from lower alkyl, lower alkoxy, or halogen; or

 where Z is Y is oxygen or sulfur; R is lower alkyl, hydroxy, loweralkoxy, hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each ofwhich is mono or disubstituted independently with halogen, thio,hydroxyl, lower alkyl, lower alkoxy, or amino; R is amino, which isunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, or amidoalkyl; heteroaryl, arylalkyl orheteroarylalkyl, each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic group having from 3-7members, where up to two of which members are heteroatoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isunsubstituted or substituted with halogen, lower alkyl or lower alkoxy;or R is a carbocyclic group having from 3-7 members, where up to threeof which members are heteroatoms selected from oxygen and nitrogen andwhere any member of the carbocyclic group is unsubstituted orsubstituted with halogen, lower alkyl, or lower alkoxy; A and B are thesame or different and represent hydrogen, or lower alkyl; and W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl.
 4. A pharmaceutical compositionaccording to claim 2 comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: n is 0 or an integer of from 1-3;X is CH, nitrogen, or oxygen; Z is an electron pair when X is oxygen; Zis hydrogen, provided that when X is CH, Z is not hydrogen; Z is aryl,which is unsubstituted or substituted with one or two groupsindependently selected from lower alkyl, lower alkoxy, or halogen; or

 where Z is Y is oxygen or sulfur; R is lower alkyl, hydroxy, loweralkoxy, hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each ofwhich is mono or disubstituted independently with halogen, thio,hydroxyl, lower alkyl, lower alkoxy, or amino; R is amino, which isunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, or amidoalkyl; heteroaryl, arylalkyl orheteroarylalkyl, each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic group having from 3-7members, where up to two of which members are heteroatoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isunsubstituted or substituted with halogen, lower alkyl or lower alkoxy;or R is a carbocyclic group having from 3-7 members, where up to threeof which members are heteroatoms selected from oxygen and nitrogen andwhere any member of the carbocyclic group is unsubstituted orsubstituted with halogen, lower alkyl, or lower alkoxy; A and B are thesame or different and represent hydrogen, or lower alkyl; and W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl.
 5. A pharmaceutical compositionaccording to claim 2 comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: X is CH, nitroge n, or oxygen; Zis an electron pair when X is oxygen; Z is hydrogen, provided that whenX is CH, Z is not hydrogen; Z is aryl, which is unsubstituted orsubstituted with one or two groups independently selected from loweralkyl, lower alkoxy, or hal ogen; or

 where Z is Y is oxygen or sulfur; R is lower alkyl, hydroxy, loweralkoxy, hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each ofwhich is mono or disubstituted independently with halogen, thio,hydroxyl, lower alkyl, lower alkoxy, or amino; R is amino, which isunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, or amidoalkyl; heteroaryl, arylalkyl orheteroarylalkyl, each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic group having from 3-7members, where up to two of which members are heteroatoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isunsubstituted or substituted with halogen, lower alkyl or lower alkoxy;or R is a carbocyclic group having from 3-7 members, wherein up to threeof the carbocyclic group are heteroatoms that are independently oxygenor nitrogen and where the carbocyclic group is unsubstituted orsubstituted with one, two, or three groups that are independentlyhalogen, lower alkyl, or lower alkoxy; and W is aryl, heteroaryl, 2- or3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is unsubstituted ormono or disubstituted independently with halogen, hydroxyl, lower alkyl,lower alkoxy, amino, or mono- or dialkylamino where each alkyl portionis lower alkyl.
 6. A pharmaceutical composition according to claim 2comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: X is CH, nitrogen, or oxygen; Zis an electron pair when X is oxygen; Z is hydrogen, provided that whenX is CH, Z is not hydrogen; Z is aryl, which is unsubstituted orsubstituted with one or two groups independently selected from loweralkyl, lower alkoxy, or halogen; or

 where Z is Y is oxygen or sulfur; R is lower alkyl, hydroxy, loweralkoxy, hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each ofwhich is mono or disubstituted independently with halogen, thio,hydroxyl, lower alkyl, lower alkoxy, or amino; R is amino, which isunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, or amidoalkyl; heteroaryl, arylalkyl orheteroarylalkyl, each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic group having from 3-7members, where up to two of which members are heteroatoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isunsubstituted or substituted with halogen, lower alkyl or lower alkoxy;or R is a carbocyclic group having from 3-7 members, where up to threeof which members are heteroatoms selected from oxygen and nitrogen andwhere any member of the carbocyclic group is which is unsubstituted orsubstituted with halogen, lower alkyl, or lower alkoxy; and W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl.
 7. A pharmaceutical compositionaccording to claim 2 comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: X is CH, or nitrogen; W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl; and R₂ and R₃ are the same ordifferent and represent hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkyl, or amidoalkyl; aryl, arylalkyl, heteroaryl, orheteroarylalkyl each of which is unsubstituted or substituted with oneor two groups that are independently halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic orcarbocyclic(C₁-C₆)alkyl group having from 3-7 members in the carbocyclicportion, where up to two of which members are heteroatoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isunsubstituted or substituted with halogen, lower alkyl or lower alkoxy.8. A pharmaceutical composition according to claim 2 comprising acompound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: X is CH, or nitrogen; W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl; and R₂ and R₃ are the same ordifferent and represent hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkyl, or amidoalkyl; aryl, arylalkyl, heteroaryl, orheteroarylalkyl each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic orcarbocyclic(C₁-C₆)alkyl group having from 3-7 members in the carbocyclicportion, where up to two of which members are heteroatoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isunsubstituted or substituted with halogen, lower alkyl or lower alkoxy.9. A pharmaceutical composition according to claim 2 comprising acompound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: A, B, C, and D are independentlyCR₁ or nitrogen, provided that no more than two of A, B, C, and D arenitrogen simultaneously; R₁ is hydrogen, lower alkyl, lower alkoxy,halogen, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, orarylalkyl; X is CH, or nitrogen; W is aryl, heteroaryl, 2- or 3-thienyl,or 2-, 3-, or 4-pyridyl, each of which is unsubstituted or mono ordisubstituted independently with halogen, hydroxyl, lower alkyl, loweralkoxy, amino, or mono- or dialkylamino where each alkyl portion islower alkyl; and R₂ and R₃ are the same or different and representhydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkyl,or amidoalkyl; aryl, arylalkyl, heteroaryl, or heteroarylalkyl each ofwhich is unsubstituted or substituted with one or two groupsindependently selected from halogen, thio, hydroxyl, lower alkyl, loweralkoxy, or amino; or a carbocyclic or carbocyclic(C₁-C₆)alkyl grouphaving from 3-7 members in the carbocyclic portion, where up to two ofwhich members are heteroatoms selected from oxygen and nitrogen andwhere any member of the carbocyclic group is unsubstituted orsubstituted with halogen, lower alkyl or lower alkoxy.
 10. Apharmaceutical composition according to claim 2 comprising a compound ofthe formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: X is CH, or nitrogen; R is loweralkyl, hydroxy, lower alkoxy, hydroxyalkyl, or aminoalkyl; R is aryl,arylalkyl, heteroaryl, or heteroarylalkyl, each of which isunsubstituted or substituted with one or two groups that areindependently halogen, thio, hydroxyl, lower alkyl, lower alkoxy, oramino; or R is a carbocyclic group having from 3-7 members, where up tothree of which members are heteroatoms selected from oxygen and nitrogenand where any member of the carbocyclic group is unsubstituted orsubstituted with halogen, lower alkyl, or lower alkoxy; and W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl.
 11. A pharmaceuticalcomposition according to claim 2 comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: X is CH, or nitrogen; W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or mono or disubstituted independently with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl portion is lower alkyl; and R₂ and R₃ are the same ordifferent and represent hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkyl, or amidoalkyl; aryl, arylalkyl, heteroaryl, orheteroarylalkyl each of which is unsubstituted or substituted with oneor two groups independently selected from halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic orcarbocyclic(C₁-C₆)alkyl group having from 3-7 members in the carbocyclicportion, where up to two of which members are heteroatoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isunsubstituted or substituted with halogen, lower alkyl or lower alkoxy.12. A pharmaceutical composition according to claim 2 comprising acompound of formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: W is aryl, heteroaryl, 2- or3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is unsubstituted orsubstituted with one or two groups that are independently halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or di loweralkylamino; Z is hydrogen; Z is aryl, which is unsubstituted orsubstituted with one or two groups that are independently lower alkyl,lower alkoxy, or halogen; or

 where Z is Y is oxygen or sulfur; R is lower alkyl, hydroxy, loweralkoxy, hydroxyalkyl, or aminoalkyl; R is aryl, arylalkyl, heteroaryl,or heteroarylalkyl, each of which is unsubstituted or substituted withone or two groups that are independently halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; R is amino, which is unsubstituted orsubstituted with one or two groups that are independently lower alkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl,or amidoalkyl, heteroaryl, C₃-C₇ cycloalkyl, or C₃-C₇ carbocyclic, eachof which is unsubstituted or substituted with one, two, or three, groupsthat are independently halogen, lower alkyl or lower alkoxy; or R is acarbocyclic group having from 3-7 members, where one, two, or threecarbon atoms are independently replaced by oxygen or nitrogen and wherethe carbocyclic group is unsubstituted or substituted with one, two, orthree groups that are independently halogen, lower alkyl, or loweralkoxy.
 13. A pharmaceutical composition according to claim 2 comprisinga compound of the formula:

or a pharmaceutically acceptable salt thereof, with at least onecarrier, adjuvant or vehicle, wherein: X is CH, or nitrogen; W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which isunsubstituted or substituted with one or two groups that areindependently halogen, hydroxyl, lower alkyl, lower alkoxy, amino, ormono- or di-lower alkylamino; and R₂ and R₃ are the same or differentand represent hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkyl, amidoalkyl; aryl, arylalkyl, heteroaryl, orheteroarylalkyl each of which is unsubstituted or substituted with oneor two groups that are independently halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; or a carbocyclic or C₃-C₇ carbocyclicC₁-C₆ alkyl group each of which is unsubstituted or substituted withone, two, or three groups that are independently halogen, lower alkyl orlower alkoxy.
 14. A method of treating anxiety, sleep disorders,overdose with benzodiazepine drugs or enhancement of memory, said methodcomprising administering a pharmaceutical composition according to claim2 to a mammal in need of such treatment.
 15. A method according to claim14 wherein the compound is:1-(5-Phenyl-thieno[3,2-b]pyridin-7-yl)-piperidine-4-carboxylic acidethylamide;1-(5-Phenyl-thieno[3,2-b]pyridin-7-yl)-piperidine-4-carboxylic acid(pyridin-4-ylmethyl)-amide;(4-Fluoro-phenyl)-{4-[5-(3-methoxy-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperazin-1-yl}-methanone;7-Morpholin-4-yl-5-phenyl-thieno[3,2-b]pyridine;7-[1,4]Diazepan-1-yl-5-phenyl-thieno[3,2-b]pyridine;{4-[5-(3-Methoxy-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperazin-1-yl}-pyridin-4-yl-methanone;4-(5-Phenyl-thieno[3,2-b]pyridin-7-yl)-piperazine-1-carbothioic acidethylamide; 1-(2-Phenyl-[1,5]naphthyridin-4-yl)-piperidine-4-carboxylicacid; 1-(5-Phenyl-thieno[3,2-b]pyridin-7-yl)-piperidine-4-carboxylicacid cyclopentylamide;2-{(N′-[1-(5-Phenyl-thieno[3,2-b]pyridin-7-yl)-piperidine-4-carbonyl]-hydrazino}-acetamide;1-(5-Phenyl-thieno[3,2-b]pyridin-7-yl)-piperidine-4-carboxylic acid(2-methoxy-ethyl)-amide;3-(2-Fluoro-phenyl)-1-[1-(5-phenyl-thieno[3,2-b]pyridin-7-yl)-piperidin-4-yl]-propan-1-one;1-(5-Phenyl-thieno[3,2-b]pyridin-7-yl)-piperidine-4-carboxylic acid(tetrahydro-furan-2-ylmethyl)-amide;1-[5-(4-Fluoro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperidine-4-carboxylicacid amide;1-[5-(4-Fluoro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperidine-4-carboxylicacid (2-methoxy-propyl)-amide;1-(6-Phenyl-thieno[2,3-b]pyridin-4-yl)-piperidine-4-carboxylic acidethylamide; or a pharmaceutically acceptable salt thereof.
 16. Apharmaceutical composition according to claim 2 wherein the compound is:N-Ethyl 1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide;N-Methyl 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(5-(2-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-4-Picolyl-1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;4-Fluorophenyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazine;N-Methylhexahydro-4-(5-phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine)-1-carboxamide;or 4-(5-Phenylthieno[3,2-b]pyridin-7-yl)morpholine.
 17. A pharmaceuticalcomposition according to claim 2 wherein the compound is:N-(3-Chloro-n-Propyl)1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-Ethyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarbothioamide;1-(2-Phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxylic acid ethylester; N-Ethyl1-(2-phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxamide; N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; N-Propyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; or1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.
 18. Apharmaceutical composition according to claim 2 wherein the compound is:N-t-Butyl 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-n-Butyl1-(5-phenylthileno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Cyclopropyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Cyclopentyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Aminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Ethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Dimethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; orN-Glycinamidyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.
 19. Apharmaceutical composition according to claim 2 wherein the compound is:N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Methoxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(3-Methoxypropyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; N-Benzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-3-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-4-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; orN-4-Methylbenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.
 20. Apharmaceutical composition according to claim 2 wherein the compound is:N-4-Ethoxybenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-4-Pyridylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Thiophenylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Tetrahydrofuranylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acid ethylester; 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylicacid;1-(5-(3-Methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;or N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.21. A pharmaceutical composition according to claim 2 wherein thecompound is;1-(5-(4-Ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Pyridinylmethyl1-(5-(4-ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(5-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Methyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Ethyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Propyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Aminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Dimethylaminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxyamide.22. A pharmaceutical composition according to claim 2 wherein thecompound is: N-(2-Hydroxyethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Methoxypropyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Ethyl1-(5-(4-pyridyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylic acid methylester; N-Ethyl1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamidehydrochloride; 5-(4-Fluorophenyl)-7-[4-(1H-imidazol-2-yl)-1-piperidinylthieno[3,2-b]pyridine;1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide;or5-(4-Fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine.23. A pharmaceutical composition according to claim 2 wherein thecompound is: N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;4-Pyridinylcarbonyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazine;N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-n-Propyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-i-Propyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;or N-n-Butyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide.